The vav proto-oncogene encodes a 95 kDa protein (p95.sup.vav) which is thought to be expressed exclusively in hematopoietic cells of all lineages and stages of maturation. p95.sup.vav has a number of interesting motifs including several src homology, leucine zipper, zinc finger, helix-loop-helix, and guanine nucleotide releasing factor domains. The presence of these domains suggests that vav serves as a transcriptional activator and/or element of the signal transduction cascade. Indeed, p95.sup.vav functions as a guanine nucleotide releasing factor in ras activation by the T-cell receptor. However, vav's function in other lineages remains unclear.
The human proto-oncogene maps to chromosome region 19p12.fwdarw.19p13.2 (Martinerie et al., Hum. Genet. 86:65-68, 1990). The vav locus was first identified by virtue of its oncogenic activation during the course of gene transfer assays using human tumor DNAs (Katzav et al., EMBO., 8:2283-2290, 1989). Molecular characterization of this oncogene allowed the isolation and characterization of its normal allele, the vav protooncogene (Coppola et al., Cell. Growth & Differ., 2:95-105, 1991; Katzav et al., Mol. Cell. Bio., 11:1912-1920, 1991). The vav proto-oncogene directs the synthesis of a 3.0 kb transcript that has been found to be specifically expressed in cells of hematopoietic origin. Removal of the helix-loop-helix sequences results in the malignant activation of the p95.sup.vav protein (Id.).
The cDNA nucleotide sequence of the vav gene and predicted 797 amino acid polypeptide are provided by Katzav et al., 1989, supra. The vav proto-oncogene nucleotide sequence of the 5' untranslated region up-stream of the translation initiation codon is disclosed in Katzav et al., 1991, Supra.
Analysis of vav gene transcripts in human cell lines has indicated that the gene is expressed in cells of hematopoietic origin; no vav gene transcripts could be observed in epithelial, mesenchymal or neuroectodermal cells (Katzav et al., 1989, supra). Lymphoid, myeloid and erythroid cell lines contained comparable levels of vav gene transcripts (Katzav et al., 1989, supra). However, the therapeutic utility of regulating vav expression has not heretofore been explored.